The aim of this application is two-fold. 1) To modify the self-administration technique developed for rats and to adapt for mice this method, which is standard for drugs of abuse studies. 2) To apply recently developed pharmacokinetic/pharmacodynamic (PK/PD) model of drug self-administration to cocaine self-administration in mice. We have shown previously that rats will self-administer the next unit dose of cocaine when the level of the drug falls to a minimum maintained level, that we term the satiety threshold. Moreover, rats will start self-administration (under condition that cue-induced lever-press behavior has been extinguished) when cocaine level exceeds the minimum reinstatement level, that we term the priming threshold. Therefore, rats display drug-seeking behavior whenever cocaine level is between these two thresholds. The cocaine priming and satiety thresholds represent phenotypic characteristics of individual rats and are comparatively stable measured for up to eight months of experimental studies. We hypothesize that absolute values of the priming and the satiety thresholds are controlled genetically and therefore may be modified by genome modification. The proposed studies will clarify the role of genes in drug-abuse vulnerability and processes of addiction.